The candidate's goal is to become an independently funded NIH investigator in biobehavioral research on obesity, with a specialization in the interaction of genetic, neural and environmental factors to influence children's appetite and weight. She is experienced in measuring children's eating behaviour and has published on genetic influences, including effects of the FTO gene. In the K99/R00, she proposes to expand her training to become competent at fMRI design and analysis, and using measures of genetic obesity risk in biobehavioral studies. The New York Obesity Research Center (NYORC), St. Luke's-Roosevelt Hospital (SLR) and Columbia University Medical Center (CUMC) are committed to Dr. Carnell's career development. She will be Assistant Professor in Psychiatry at SLR on activation of the award, and will obtain further advice on advancement from formal mentors and via informal mentorship from other junior and senior investigators in the CU research network. Dr. Carnell currently has a J1 visa, and will move to an H1-B visa to enable her to be productive in the US for the full K99/R00 period. By the end of the award, she will have permanent residence status. The research environment and collaborators are well-suited to Dr. Carnell's interests. Her proposed Mentor for the K99 is Dr. Allan Geliebter, an expert in the role of gut hormones in eating disorders and obesity, and well-published author in neuroimaging of obesity. Her Co-mentor is Dr. Wendy Chung, well-known for basic research on genetic influences on obesity in rodents and humans. Facilities available via NYORC include Molecular Genetic and Hormone-Metabolite Core Labs, which handle genotyping and hormone assays at minimal cost for NIH investigators. Dr. Carnell can use the MRI unit at the New York State Psychiatric Institute (NYSPI) for neuroimaging, and the Adolescent Health Clinic at CUMC for recruitment, medicals, and hormone collections. Collaborators Dr. Brad Peterson (CUMC fMRI research) and Dr. Karen Soren (CUMC Adolescent Medicine) will facilitate use of these services. Training available includes courses on neuroimaging, and genetics (CU);fMRI analysis journal club (CUMC/ NYSPI);seminars on obesity research (NYORC) and appetitive behavior (CU);and department-specific grand rounds (CUMC and SLR). Dr. Carnell's goal during the K99/R00 grant is to submit applications as PI on additional R mechanism grants and by the end to apply competitively for an R01. The aim of the K99 project is to study the neural mechanisms underlying increased intake of high energy dense (ED) foods in obese adolescents as well as in lean adolescents who are at high risk of obesity due to maternal obesity. She will investigate whether abnormalities in brain activation are already present in the high risk adolescents, suggesting a causal role for these factors in weight gain. K99 participants (Subjects;Ss) will be 22 (11M;11F) obese (BMI centile>95th) and 44 (22M;22F) lean (BMI centile<85th) postpubertal 14-18 yr olds, recruited from the CUMC adolescent outpatient clinic, and their mothers. Of the lean Ss, 22 (11M;11F) will have low familial risk (LFR) for obesity (lean biological mother), and 22 (11M;11F) will have high familial risk (HFR) for obesity (obese biological mother). Ss deemed eligible after brief screening and an initial consultation will be invited to a testing day. At 8:30 am, Ss will consume 400 ml of Boost (high protein liquid meal) to ensure moderate satiety. At 10:30 am, functional brain activity (fMRI) in response to visual high ED food cues (e.g. pizza), low ED food cues (e.g. fruits), and non-food cues (office supplies) will be assessed using a 3T fMRI scanner. In response to high ED food cues (relative to low ED and non-food cues), obese Ss are expected to show greater activation relative to lean Ss in the insula, orbitofrontal cortex, amygdala, hippocampus, and striatum (appetitive reward), and less activation in the dorsolateral prefrontal cortex (inhibition of food intake) and posterior hypothalamus (satiety). Lean HFR Ss are expected to show greater activation relative to lean LFR Ss in appetitive reward areas, and less activation in satiety/inhibition of food intake areas, reflecting differences in the processing of food stimuli which may lead to obesity. The aim of the R00 is to build on the K99 to investigate neural pathways associated with genetic obesity risk which could mediate the effect of genes on appetite and weight. Buccal samples will be collected from 300 lean (BMI centile<85th) 14-18 yr olds, and used to genotype common obesity-associated variants (e.g., FTO). Genetic burden scores (GBS) will be generated by multiplying the genotype at each locus by its per allele effect on BMI;those in the upper (HGR) and lower (LGR) quintiles will be eligible. 88 (44M;44F) completers are anticipated: 44 (22 obese, 22 lean) at high genetic risk for obesity (HGR), and 44 (22 obese, 22 lean) at low genetic risk (LGR). Procedures will follow the K99 but there will be a "fed" condition, where Ss consume 400 ml Boost 1 hr before the scan, and a "fasted" condition (400 ml water). Fasting levels of gut hormones will be assessed during the physical. Ghrelin is expected to be higher in HGR than LGR Ss, and PYY and GLP-1 higher in LGR. HGR are expected to show, to a greater degree in the fed state, greater activation relative to LGR in appetitive reward areas and less activation in satiety/inhibition of food intake areas, independent of current adiposity. PUBLIC HEALTH RELEVANCE: 18% of US adolescents and 33% of US adults are obese. To prevent and treat obesity we need to understand the biology of overeating and obesity. The proposed project will investigate the brain processes underlying excessive intake of high energy foods in obese adolescents and those at high risk of becoming obese. The results may lead to new drugs and interventions to improve eating behavior, and help establish unbiased indicators of obesity risk and prognosis for use in research and clinical settings.